Abstract

Background Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either
in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according
to the features of background liver.

Objective To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in liver carcinogenesis.

Methods Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation
and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according
to the condition of the background liver (presence or absence of significant fibrosis).

Results Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than
in HCC/HCV (60% vs 20%, p<0.01). Advanced fibrosis/cirrhosis in the peritumoral liver was the only clinicopathological factor
associated with the 6p21.1 amplicon in HCC/MS. Increased expression of cullin7 (CUL7), a gene located at the 6p21.1 locus,
was demonstrated in HCC with the 6p21.1 amplicon, in parallel with a decrease in cyclin D1 expression. CUL7 downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its
degradation), decreased cell proliferation and increased apoptosis.

Conclusions This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in liver carcinogenesis associated with MS, the amplification of which might influence
cell proliferation.